PROJECT SUMMARY/ABSTRACT In this project, we will evaluate the trajectory of changes in regional oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis or AG) and in brain circulation through the course of preclinical AD to symptomatic AD in late middle-aged and older adults. It is currently established that AG is a marker of a group of metabolic functions which includes biosynthesis, neuroprotection, and apoptosis, which, in the context of the normal brain is involved in synaptic remodeling, learning and memory, and generation of energy for membrane pumps. AG is about 10-15% in the normal adult human brain, and it demonstrates more substantial changes compared to other measures of brain metabolism in response to physiological activation or pathophysiological challenges associated with brain diseases. Our cross-sectional observations in cognitively normal adults suggest that areas of the human brain targeted by AD pathology have uniquely high levels of AG, and higher levels of AG are associated with less PIB deposition, higher levels of CSF A?42 and better scores on cognitive tests. In our current project, we will determine the role of AG as a potential early biomarker of evolving AD pathology and predictor of cognitive decline. Our specific aims include estimation for the first time of AG in individuals with mild-to-moderate symptomatic AD combined with that in cognitively normal individuals to evaluate a hypothesis that low baseline AG will be associated with the subsequent development of AD pathology and cognitive decline. We will also determine the relationship between the rate of change in AG and rate of change in clinical assessments and biomarkers of AD. In most cases, this information will be combined with the previously collected data in the same individuals to provide a multipoint trajectory over time. These longitudinal assessments will allow us to evaluate changes in AG and other PET measures of metabolism and circulation during the transition from no AD pathology to preclinical AD, and through the preclinical stages to symptomatic AD. We will evaluate the hypothesis that AG changes prior to other parameters, and that the rate of change in AG will predict progression in AD pathology and cognitive decline. Our work may not only expand significantly our understanding of the role of glucose in brain function beyond providing energy via oxidative phosphorylation, but also provide important new insights into the pathophysiology of AD and neuroprotective potential of AG. This project is innovative because it proposes to combine different biomarkers of AD to address novel questions, in vivo, in humans to produce findings relevant to both clinical disorders and fundamental human neurophysiology. The methods chosen, with which our group has substantial expertise, will allow us to study intrinsic regional brain activity and energy utilization, in vivo, in humans, which appear to be associated with the regional development of AD pathology. This project will evaluate a potential of AG as a highly specific biomarker of synaptic function, and provide novel insight into the development and control of the efficacy of preventive treatments aimed to reduce AD pathology by modulating synaptic function.